Iontophoresis device and drug unit

ABSTRACT

Herein disclosed is an iontophoresis device suitable for effective use of a drug supported on a drug support. A donor electrode-printed portion ( 6 ) and a reference electrode-printed portion ( 7 ) are arranged on a backing layer ( 4 ). The backing layer is provided with, at the periphery, an adhesive film ( 3 ) for fixing a pharmaceutical preparation to an application site. The both electrode-printed portions ( 6 ), ( 7 ) are electrically connected to a current-generating portion (Ia) through a conductive snap connector (Id). The drug support ( 14 ) is removably joined with a conductive layer ( 11 ) formed on the electrode on the side of the donor electrode-printed portion ( 6 ). The drug support ( 14 ) is subjected to a drug diffusion-inhibitory treatment ( 30 ).

TECHNICAL FIELD

The present invention relates to an iontophoresis device suitable forthe percutaneous administration and the application through the mucousmembranes and in particular to an iontophoresis device activated uponthe practical use.

BACKGROUND ART

Recently, there have been developed a variety of dosage forms in thefield of pharmaceutical preparations for external use and thedevelopment of dosage forms has gradually become a matter of greatconcern. The reason for this is as follows: The administration of adrug, which may have a local or systemic pharmacological action, throughthe skin or the mucous membranes has many advantages. For instance, thesustained-release effect of the drug can be expected; suchadministration is not greatly influenced by the metabolism due to thefirst-pass effect in the liver unlike the oral administration andpermits the effective use of the drug; and drugs accompanied by, forinstance, liver disorders can relatively safely be administered to apatient.

However the normal skin naturally has a protective effect againstexternal stimulations and this makes the absorption and penetration of adrug through the skin relatively difficult. For this reason, in theexisting circumstances, a drug is not absorbed in an amount sufficientfor ensuring a satisfactory effect even if the drug is administered to apatient in a dosage form for external use. Moreover, in theadministration method, which makes use of absorption routes throughbiological membranes other than the skin, such as mouth, rectum, oralcavity and nose as well as the sublingual route, it is difficult topenetrate into or transmit through the related biological membranesdepending on the kinds of drugs and therefore, there have been known alarge number of drugs having low bioavailability. Accordingly, there hasbeen desired for the development of an absorption-promoting method,which can sufficiently enhance the permeability, penetrability andabsorbency of a drug against the skin and other biological membranes,can ensure a sufficient pharmacological efficacy of the drug and issubstantially free of, for instance, its local and systemic toxicity andis highly useful and safe.

As such absorption-promoting methods, there have recently been knownchemically promoting methods, which make use of absorption-promotingagents, and physically promoting methods in which iontophoresis orphonophoresis techniques are employed. Among these, the iontophoresistechnique has unexpectedly attracted special interest recently and hasbeen expected as an administration method, which can solve the foregoingproblems.

The iontophoresis technique is a method for the administration of a drugby applying an electric voltage to the skin or a mucous membrane toelectrically induce the migration of an ionic drug and to thusadministrate the drug through the skin or a mucous membrane. In general,an iontophoresis device is provided with a pair of electrode foriontophoresis, i.e., an anode and a cathode and the device is sodesigned that these electrodes are arranged on or attached to the skinat a predetermined distance apart from one another and an electriccurrent generated by a current generator is guided to these electrodesto thus effect treatments of patients.

Moreover, this iontophoresis device has a structure which comprises acombination of these electrodes and a layer, which stores a drugtherein, and avariety of additives for maintaining the drug efficacyare, if necessary, enclosed in the layer in addition to a predeterminedamount of the effective component in order to keep a desired bloodconcentration in the body over a long period of time.

It has been a recent tendency to study the administration, by theiontophoresis, of polypeptide type drugs, which should be administeredin a time control or intermittent type mode. Originally, thephysiologically active peptides and proteins are decomposed by thedigestive juice in the gastrointestinal tracts and simultaneouslyhydrolyzed by the hydrolases present on the wall of the digestive tract.For this reason, it is difficult to improve the absorption efficiency ofthese drugs and it is the leading mainstream in the medical field toadminister the drugs not orally, but through injection. However, theadministration through injection would give a heavy physical burden to apatient and is not always a treating method of a high compliance.Contrary to this, the iontophoresis permits the establishment of anyabsorption pattern by strictly controlling the electrical charging timeand is an effective percutaneous absorption system which can realize aneffective drug treatment, while taking into consideration the circadianrhythm, in particular, in the treatment in which an endogenous compoundis supplemented. Therefore, if an iontophoresis device that permits theadministration of drugs by a patient per se can be developed, it wouldbe possibly to open the way for the home treatment.

According to the conventional studies, there have been proposed a largenumber of techniques relating to drug supports, which takes, intoconsideration, the instability of polypeptide type drugs to water andthe high adsorbing ability thereof. For instance, Japanese Un-ExaminedPatent Publication Nos. Hei 2-218375 and Hei 2-206473 disclose drugsupports capable of being electrically communicated with an electrode onthe drug-administration side and capable of being brought into contactwith the skin. As the drug supports of this type, there have been known,for instance, those constituted by organic members and those constitutedby inorganic members. In addition, as methods for applying a drug to thedrug support, there have been used, for instance, methods for coatingthe support with a drug or impregnating the support with a drug; ormethods for applying a drug by drying or half-drying.

In these methods, however, it has been believed that drugs such asphysiologically active peptides or proteins may be adsorbed on the drugsupport and accordingly, the rate of transdermal absorption of the drugis reduced. For this reason, there have also been proposed manytechniques for solving the problem of the adsorption of drugs on thedrug support. For instance, Japanese Un-Examined Patent Publication No.Hei 6-16535 discloses a technique comprising the step of coatingaporousorcapillarystructuremadeof anon-conductivematerial with ahighmolecular weight protein such as bovine serum albumin, human serumalbumin or gelatin. Moreover, Japanese Un-Examined Patent PublicationNo. Hei 8-98894 discloses an interface for the iontophoresis device inwhich a coating layer of an ionic surfactant is formed on a drug supportmaterial. In addition, Japanese Un-Examined Patent Publication No. Hei9-56827 discloses an interface for the iontophoresis device in which aphysiologically active peptide is deposited on or applied to a thin filmhaving an average pore size ranging from 0.1 to 15 μm, a porosityranging from 65 to 90% and a low protein adsorptivity. Moreover,Japanese Un-Examined Patent Publication No. Hei 9-77658 discloses atechnique comprising the step of applying a drug onto a hydrophobic areaformed on a part of a hydrophilic film to thus give a transdermallyabsorbable pharmaceutical preparation.

In the conventional techniques, however, the drug support is in anexposed state and therefore, the drug is lost by any physical contactand through adsorption on the skin of a patient by any accidental touchwith hands upon the application thereof, even if the drug in the driedcondition is supported on the drug support. Moreover, when a drugsupport, which makes use of a porous hydrophilic film, is used and whena drug solution is supplied to the drug support or a drug included inthe drug supportinthedriedconditionisre-dissolved, thedrugsolutiondiffuses from the center of the drug support to the periphery thereofdue to the capillary phenomenon. Therefore, such a drug support suffersfrom a problem in that the drug solution moves towards an adhesive layer(for fitting the support to the skin) disposed at the periphery of thesupport and the amount of the drug to be used for the treatment isreduced.

On the other hand, when it is intended to incorporate, into a drugsupport, a drug having a high adsorbing ability and unstable tomoisture, care should be taken not to lose a drug solution due to themovement thereof to other members during the term extending from theapplication of the drug to the completion of the drying. Otherwise thedrug would be lost. It is necessary to prevent any movement of the drugtowards other members during storing the drug support, or any movementof the drug towards other members during assemblage (or preparation) ofa pharmaceutical preparation dissolved immediately before the practicaluse and during usage (during treatment), for the same reason.

In addition, it is sometimes observed that when the drug support isjoined to the drug-dissolving portion, the air, which penetrates intothe joint plane, would inhibit uniform dissolution of the drug andaccordingly, the application of the device never ensures any sufficientdrug efficacy. This would likewise be considered to be a drug loss in awide sense and such insufficient dissolution of the drug present in thedrug support would inhibit the effective use of the drug. Moreover, theelectrical charging of the device is non-uniform due to the airpenetration and there is sometimes observed skin stimulations uponpractical use. The inventors of this invention were the first researchworkers to experience such a problem during studying and developing aniontophoresis device and there has never been known any prior art whichrefers to this problem.

Accordingly, it is an object of the present invention to provide aniontophoresis device suitable for effective use of a drug incorporatedinto a drug support as well as a drug unit.

DISCLOSURE OF THE INVENTION

The foregoing object of the invention can be accomplished by providingan iontophoresis device which comprises a drug-dissolving portion havinga drug-activation function and a drug support subjected to a treatmentfor inhibiting any drug diffusion and/or a treatment for exhausting airand removably connected to the drug dissolving portion.

Thus, if the drug support is subjected to a drug diffusion-inhibitorytreatment, the dissolved drug does not migrate to other members and thedrug may efficiently be used. In addition, if the drug support issubjected to a treatment for exhausting any air, any air present isexhausted when the drug-dissolving portion is joined to the drug supportand the drug is uniformly dissolved. Therefore, the drug can likewiseefficiently be used in this case.

In this respect, the drug support can be subjected to a drugdiffusion-inhibitory treatment by disposing a resin part or a thermallycompressible portion at the periphery of the drug support. In addition,the air-exhausting treatment may comprise the step of forming an airvent hole at the periphery of the drug support.

Moreover, the drug support prior to the practical use is provided in theform housed in a drug unit. This drug unit is provided with members suchas a drug support for accommodating a drug, a cover placed on one sideof the drug support, a cover placed on the other side of the support andan adhesive for removably fixing the both covers to the drug support.These covers also serves as members for protecting the drug support andthus examples thereof usable herein are liners and caps or lids coveringor put on the drug support. In addition, if necessary, the cover may besubjected to a drug adsorption-inhibitory processing or a drying agentfor maintaining drugs in the dry condition may be positioned within thedrug unit. Such a construction of the drug unit permits the protectionof the drug support from any touch with hands and/or any physicalcontact immediately before the practical use. In addition, theconstruction also prevents any transfer of the drug to other members andcan maintain the drug in its dry state. Thus, the drug support allowsthe effective use of the drug accommodated therein.

BRIEF DESCRIPION OF THE DRAWINGS

FIG. 1 is a diagram showing the cross sectional structure of aniontophoresis device according to the present invention upon itspractical use.

FIG. 2 is a diagram showing an embodiment of a drug unit in which (a),(b) and (c) are a view of the surface, an internal view and a crosssectional view of the drug unit, respectively.

FIG. 3 is a diagram showing another embodiment of a drug unit in which(a), (b) and (c) are a view of the surface, an internal view and a crosssectional view of the drug unit, respectively.

FIG. 4 is a diagram showing still another embodiment of a drug unit inwhich (a), (b) and (c) are a view of the surface, an internal view and across sectional view of the drug unit, respectively.

FIG. 5 is a diagram showing a variety of embodiments of the method forsubjecting a drug support to a drug diffusion-inhibitory treatment, inwhich (a), (c), (e) and (g) are views of the surface of the support and(b), (d), (f) and (h) are cross sectional views thereof.

FIG. 6 is a diagram showing a variety of embodiments of the method forsubjecting a drug support and an adhesive layer to an air-exhaustingtreatment, in which (a), (c), (e) and (g) are views of the surface ofthe support and (b), (d), (f) and (h) are cross sectional views thereof.

FIG. 7 is a diagram showing an embodiment of the configuration of acurrent-generating portion Ia, in which (a), (b) and (c) are a view ofthe surface, a view of the back face and a cross sectional view of theportion, respectively.

FIG. 8 is a diagram showing an embodiment of the configuration of anintegrated electrode portion Ib, in which (a), (b), (c) and (d) are aview of the surface, an internal view, a view of the back face and across sectional view of the electrode portion, respectively.

FIG. 9 is a diagram showing an embodiment of the configuration of aconductive snap connector Id, in which (a) and (b) are a view of thesurface and a cross sectional view of the connector, respectively.

FIG. 10 is a diagram showing an embodiment of the configuration of anauxiliary stand for assemblage Ie-1, in which (a) and (b) are a view ofthe surface and a cross sectional view of the connector, respectively.

FIG. 11 is a diagram showing an embodiment of the configuration of anauxiliary stand for assemblage Ie-2, in which (a) and (b) are a view ofthe surface and a cross sectional view of the connector, respectively.

FIG. 12 is a diagram showing an embodiment of the method for assemblingan iontophoresis device, which makes use of a drug unit Ic-1, in which(a) shows the first half of the assembling process and (b) shows thesecond half of the assembling process, respectively.

FIG. 13 is a diagram showing an embodiment of the method for assemblingan iontophoresis device, which makes use of a drug unit Ic-2, in which(a) shows the first half of the assembling process and (b) shows thesecond half of the assembling process, respectively.

FIG. 14 is a graph showing changes, with time, of the concentration ofhPTH (1-34) in the serum observed in Test Example 3.

BEST MODE FOR CARRYING OUT THE INVENTION

FIG. 1 is a diagram showing the cross sectional structure of aniontophoresis device according to the present invention upon itspractical use. In this figure, every part is depicted separately tomake, easier, the understanding of these parts, which are in fact in alaminated relation or come in close contact with one another.

In this figure, a donor electrode-printed portion 6 is positioned on oneside of a backing layer 4 and a reference electrode-printed portion 7 ispositioned on the other side of the layer 4. An adhesive film 3 such asa medical adhesive tape is disposed on the periphery of the backinglayer 4 for securing a pharmaceutical preparation to an applicationsite. The both electrode-printed portions 6, 7 are connected to acurrent-generating portion Ia through a conductive snap connector Id.The donor electrode-printed portion 6 on the backing layer 4 is providedwith a conductive layer 11 (a drug-dissolving portion) on the donorelectrode side, while the reference electrode-printed portion 7 isprovided with a conductive layer 10 on the reference electrode side. Adrug support 14 is removably connected to the drug-dissolving portion11. An adhesive layer 13 is formed on a part of the drug support 14,whereby the drug support 14 is fixed to the backing layer 4 or the donorelectrode-printed portion 6.

The iontophoresis device having such a structure discussed above isadhered to, for instance, the skin 40 upon the practical use thereof, asshown in FIG. 1. At this stage, the drug, which is in a dry conditionand supported on the drug support 14, is dissolved in the water suppliedfrom the drug-dissolving portion 11. Since the periphery of the drugsupport 14 is subjected to a drug diffusion-inhibitory treatment 30, thedrug remains at a desired position on the drug support 14 withoutcausing any migration towards other members. Moreover, the air isremoved from the joined region between the drug-dissolving portion 11and the drug support 14 since the drug support 14 has been subjected toan air-exhausting treatment (not shown). Then a power supply for thecurrent-generating portion Ia is switched on to thus put theiontophoresis device in operation.

In this respect, the drug support 14 is accommodated in the drug unitprior to the practical use as will be detailed below and thus separatedfrom the drug-dissolving portion 11. Accordingly, even if the drugsupport comprises a drug (such as physiologically active peptides) whosestability to water is insufficient, it is not necessary to be anxiousabout decomposition of the drug with time due to the moisture present inthe drug-dissolving portion.

The drug dissolved in the water supplied from the drug-dissolvingportion never migrates to other members of the device since theperiphery of the drug support is subjected to a drugdiffusion-inhibitory treatment. In addition, any air does not penetrateinto the joined region between the drug-dissolving portion and the drugsupport because of the air-exhausting treatment and therefore, the drugcan uniformly be dissolved in the water originated from thedrug-dissolving portion. Thus, the drug accommodated in the drug supportcan efficiently be used.

We will now explain, in detail, Examples of drug units, in which such adrug support 14 is accommodated. Detailed structures of other portionsand methods for assembling the device will be described below.

EXAMPLE 1

FIG. 2 is a diagram showing an embodiment of a drug unit in which (a),(b) and (c) are a view of the surface, an internal view and a crosssectional view of the drug unit, respectively. The drug unit (Ic-1)according to this Example is formed by sandwiching a porous drug support14 between a liner 17 on the electrode side anda liner 12 on the skinside. In this connection, the liner 17 on the electrode side is providedwith a perforation for folding the liner, while the liner 12 on the skinside is provided with two insertion openings 15 for a conductive snapconnector as will be explained below and a perforation 16 for pullingout the liner after the completion of the assemblage. Either of theseliners herein used may be a film having low drug-adsorptivepropertiessuchaspolyethyleneterephthalate. The drug is adhered to and supported bythe drug support 14 by a method comprising the steps of, for instance,spraying or impregnating the support with a drug solution through anopening 18 for the application of the solution. In this respect, a coverfor sealing may close the opening 18 for the application of a drugsolution after the application of the drug in order to maintain theperiphery of the drug support 14 under the dry condition. Moreover,Adhesive layers 13 are disposed on both sides of the periphery of thedrug support in order to adhere the electrode portion to the skin andthe coated pattern of the adhesive layer 13 is a stripe coating forensuring the air exhaustion. In this connection, the side of each liner12, 17, which comes in contact with the drug support 14, is subjected toa treatment 12′, 17′ with silicone in order to prevent any drugadsorption and to improve the peeling ability thereof. Moreover, theliners are also subjected to a drug diffusion-inhibitory treatment 30 toprevent any spreading of the drug solution towards the adhesive layer.

EXAMPLE 2

FIG. 3 is a diagram showing another embodiment of a drug unit in which(a), (b) and (c) are a view of the surface, an internal view and a crosssectional view of the drug unit, respectively. Sandwiching a porous drugsupport 14 between a liner 17 on the electrode side and a liner 12 onthe skin side forms the drug unit (Ic-2) according to this embodiment.The liner 17 is provided with an opening 18 for the application of adrug solution. In addition, the side, of the drug support 14, of eachliner 12, 17 is subjected to a treatment 12′, 17′ with silicone toprevent any drug adsorption and adhesive layers 13 are disposed on theboth sides of the drug support 14. In this respect, Example 2 isidentical to Example 1. However, Example 2 is substantially differentfrom Example 1 in that both of the liners are fabricated and designed insuch a manner that they do not come in direct contact with the drugsupport 14. A drying agent 19 (such as a patch type-drying agent) isdisposed on the inner side of the fabricated liner 12.

EXAMPLE 3

FIG. 4 is a diagram showing still another embodiment of a drug unit inwhich (a), (b) and (c) are a view of the surface, an internal view and across sectional view of the drug unit, respectively. In the drug unit(Ic-3) according to this Example, The configuration of the unit isidentical to those disclosed in Examples 1 and 2 except that thestructure of the liner differs from those used in Examples 1 and 2. Theliner of. this Example is constituted by an integrally molded liner 20and divided into a molded portion and a flat portion, which borderacross a folding axis 23. In other words, the liner is designed suchthat the drug support is sandwiched between the molded and flat portionsupon storing the same. In addition, a fixing terminal 22 and an opening21 for inserting the fixing terminal are formed as a member for fixingthe liner after sandwiching the drug support. Moreover, the integrallymolded liner 20 comprises a conventional plastic film and a drycomponent-containing layer 20′ laminated with the film so that theinterior of the drug unit is maintained in its dry condition. Inprinciple, this Example does not require the use of any drying agent,but a drying agent may be used in combination.

EXAMPLE 4

FIG. 5 is a diagram showing a variety of embodiments of the method forsubjecting a drug support to a drug diffusion-inhibitory treatment. Inthis Example, the drug support 14 is composed of a porous film material.In this figure, (a), (c), (e) and (g) are views of the surface of thesupport and (b), (d), (f) and (h) are cross sectional views thereof.

In an embodiment Ma-1, the diffusion-inhibitory treatment 30 comprises,as shown in FIGS. 5(a) and (b), the step of partially applying athermosetting water-repellent resin (such as a silicone resin) to aregion adjacent to the interior of the adhesive layer 13 of the drugsupport 14 or printing the region with the resin to thus close thepores.

In an embodiment Ma-2, the drug support 14 is treated by the same methoddescribed above, as shown in FIGS. 5(c) and (d). In this case, however,the drug support is further entirely subjected to a diffusion-inhibitorytreatment 30 in a mesh-like pattern in order to uniformly disperse adrug solution on the drug support 14.

In an embodiment Ma-3, the diffusion-inhibitory treatment 30 comprisesthe step of partially subjecting the drug support 14 to a thermalcompression treatment, as shown in FIGS. 5(e) and (f), to thus eliminateany pores of the support. In this Example, unevenness is simultaneouslyimparted to the porous film material during the treatment. According tothis Example, any diffusion of the drug solution can be prevented by theelimination of the pores and the formation of unevenness by the thermalcompression treatment.

In an embodiment Ma-4, the diffusion-inhibitory treatment 30 comprises,as shown in FIGS. 5(g) and (h) the combination of a partial compressiontreatment of the drug support 14 and amethod comprising cutting through,for instance, a perforation. In this case, the perforation is formed onthe exterior of the thermally compressed portion corresponding to anon-conductive region.

The shape and width of the pattern formed by the diffusion-inhibitorytreatment 30 are not restricted to any specific one. The pattern isdesirably a circular shape having a width ranging from 0.5 to 1.5 mm. Inthis Example, 4 embodiments of the diffusion-inhibitory treatment havebeen described, but the treatment is not restricted to these specificembodiments and the treating methods and the processed patterns mayarbitrarily be combined or changed.

EXAMPLE 5

FIG. 6 is a diagram showing a variety of embodiments of the method forsubjecting a drug support 14 and an adhesive layer 13 to anair-exhausting treatment, in which (a), (c), (e) and (g) are views ofthe surface of the support and adhesive layer; and (b), (d), (f) and (h)are cross sectional views thereof.

In an embodiment Mb-1, the adhesive layer 13 positioned in a regionadjacent to the exterior of a region of the drug support 14 subjected toa diffusion-inhibitory treatment 30 (thermal compression) is subjectedto an air-exhausting treatment 31 such as a stripe coating, as shown inFIGS. 6(a) and (b).

In an embodiment Mb-2, four air-exhausting holes, as regions subjectedto an air-exhausting treatment 31, are formed between the regionsubjected to the diffusion-inhibitory treatment 30 (thermal compression)and the adhesive layer and further the adhesive layer 13 is subjected toa stripe coating treatment for air-exhaustion, as shown in FIGS. 6(c) an(d). A desired effect can be expected by forming at least two holes, assuch air-exhausting holes, having a diameter of 1 mm or less.

In an embodiment Mb-3, four air-exhausting holes are formed within theregion subjected to the diffusion-inhibitory treatment 30 (thermalcompression treatment), as regions subjected to an air-exhaustingtreatment 31 and uncoated portions 32 for air-exhaustion are formed onthe adhesive layer 13, as shown in FIGS. 6(e) and (f).

In an embodiment Mb-4, a notch is formed on the adhesive layer 13, whichhas been subjected to a stripe coating as an air-exhausting treatment31, through the drug support 14, as shown in FIGS. 6(g) and (h). In thisembodiment, the effect of air-exhaustion through the adhesive layer 13is further improved. In any case, the regions subjected to theair-exhausting treatment are formed such that the conductive portioncontaining a drug solution is electrically isolated and therefore, thereis not any possibility of causing a leakage of electricity through theregions, which have been subjected to such an air-exhausting treatment.

In case where the adhesive layer 13 is subjected to the foregoingpattern coating (intermittent coating, stripe coating, intermittentstripe coating), the width of the intermittent pattern is not restrictedto any particular range insofar as a good balance between the adhesiveforce and air-permeability is established, but it is desirably rangesfrom 0.1 to 20 mm. It is also possible to make a cut such as aperforation, in addition to the foregoing methods. The shape of the cutis not restricted to any particular one. However, a circular perforationis desirably formed, which has a width ranging from 0.5 to 2 mm. In thisExample, four embodiments are illustrated as a method for subjecting thedrug support 14 to an air-exhausting treatment, but the presentinvention is not restricted to these embodiments. More specifically, thetreating methods and the processed patterns may arbitrarily be combinedor changed.

We will hereunder explain, in detail, materials or the like of each partof the drug unit as shown in FIGS. 2 to 6.

The adhesive layer 13 may be formed using adhesives used for forming anadhesive film 3 as will be detailed below. This layer can be formed bypattern coating (intermittent coating, stripe coating,intermittent-stripe coating) and the layer desirably has a structure,through which air easily passes. The width of the intermittent patternformed by the pattern coating is not restricted to any particular rangeinsofar as a good balance between the adhesive force andair-permeability is established, but it is desirably ranges from 0.1 to20 mm.

The drug support 14 may support a drug consisting of a physiologicallyactive substance and may be formed from any material insofar as the drugmay pass through the material. In case where the drug is aphysiologically active substance or a protein, a hydrophilic porousmaterial may be used for forming the support 14 and the material cansupport drugs in dry states and has low adsorptivity. The hydrophilicfilm formed from such a hydrophilic porous material includes a thin filmhaving high wettability by water such as a hydrophilized hydrophobic (orwater-repellent) polymer thin film or a hydrophilic substance-containinghydrophilic polymer film.

Examples of hydrophilized hydrophobic polymer thin films are thin filmsformed from hydrophilized fluoroplastics (such as hydrophilic DURAPOREavailable from Millipore Company and hydrophilicpoly(tetrafluoroethylene) available from Toyo Roshi Co., Ltd.), thinfilms such as those formed from hydrophilic polyther sulfone (such asSupor available from German Science Company) and hydrophilized cellulosederivatives (such as hydrophilized cellulose monoacetate andhydrophilized cellulose triacetate).

Examples of hydrophilic substance-containing hydrophilic polymer thinfilms include a variety of polymers obtained by adding appropriatesurfactants and impregnating therewith and then drying, for instance,hydrophilized cellulose acetate films (such as Asymmetric Ultra Filteravailable from sartorius Company and cellulose acetate type onesavailable from Toyo Roshi Co., Ltd.), hydrophilized polycarbonate films(such as Isopore Membranes available from Nihon Millipore Ltd.),hydrophilized poly (tetrafluoroethylene) films (such as OmniporeMembranes available from Millipore Company), hydrophilized polysulfonefilms (such as HT Tuffryn available from Gelman Sciences Inc.) andhydrophilized nonwoven fabrics (such as films obtained by coatingpolyester nonwoven fabrics with cellulose acetate (e.g., coated typemembranes available from Toyo Roshi Co., Ltd.)). The hydrophilic filmsalso include, for instance, nylon films (such as BIODYNE available fromNihon PALL Ltd.).

Incidentally, drugs unstable to water should desirably be included in oradhered to the drug support in their dry state in order to improve thestability of these drugs and to inhibit any leakage and deteriorationthereof. On the other hand, in case of drugs stable to water, they maybe supported on the drug support in their gel-like conditions. In such agel-like drug support, suitably used herein are water-soluble polymersand hydrogel thereof. A method for preparing such a gel-like drugsupport comprises the step of mixing and kneading a gelling agent suchas a water-soluble polymer and a drug solution. Moreover, the electricalconductivity of the gel-like drug support can be enhanced by addition ofan electrolyte such as sodium chloride, potassium chloride, sodiumcarbonate, phosphoric acid or sodium citrate; or a pH-buffering agentsuch as acetic acid, sodium acetate, phosphoric acid, sodium phosphate,citric acid or sodium citrate. Moreover, the kneaded mixture is formedinto a product to such an extent that it has a selfshape-maintainability and then spreaded into a sheet or a film. If thekneaded mixture has an insufficient self shape-maintainability,amesh-like support maybe incorporated into the gel. The thickness of thegel layer desirably ranges from 0.1 to 2 mm and particularly preferably0.3 to 0.8 mm. If it is too thin, the gel strength is considerably low,while if it is too thick, the movement of the drug is inhibited andaccordingly, the rate of drug absorption is reduced.

In the present invention, the drug unit is provided therein with aprotective member, which is designed to permit the arrangement of adrying agent 19. The role of the protective member is to store a drugunstable to water in its dry state and to thus improve the storagestability thereof. Further, the protective member serves to protect thedrug support from any external impact. The protective member isspecifically a liner such as those described above and a productobtained by molding and processing a film. The drying agent is arrangedin the drug unit without coming in close contact with the drug support.

The liners 12, 17 as the protective members may be any one insofar asthey are formed from awater-impermeable material, but are desirablythose capable of being processed through molding (such as thermalmolding and vacuum molding). Examples of such water-impermeablematerials usable herein are aluminum foils, polyester films,polypropylene films and polyethylene films as well as laminated filmsthereof. In addition, it is desirable to use these materials aftersubjecting them to an adsorption-inhibitory treatment such as atreatment with silicone or Teflon. This treatment would facilitate thepeeling off thereof from the adhesive layer.

As the drying agent 19, there may be used a patch type one and this ispositioned on the inside of the protective member. The drying agents arenot limited to any particular one insofar as they do not adverselyaffect the efficacy of the drug and examples thereof preferably usedherein are those having strong drying ability and strong hygroscopicityor an ability of absorbing moisture within a short period of time, suchas silica gel, alumina and zeolite. Moreover, the drying agent in theform of particles or powder may be packed in, for instance, paper ornonwoven fabrics or enclosed in a container. Preferably, the dryingagent or package thereof is provided with an adhesive layer for theinstallation thereof.

Moreover, the use of a plastic film laminated with a dryingcomponent-containing layer, as a protective member, permits themaintenance of the interior of the drug unit in the dry condition.Examples of the drying components usable herein are those, which mayadversely affect the drugs (the liquefaction of the drying componentsdue to their deliquescence) and thus cannot be used in the package ofthe drying agents, such as calcium chloride, magnesium sulfate, aluminumoxide and barium oxide, not to speak of the components of the dryingagents listed above. Moreover, the drying component-containing layer maybe a product obtained by mixing and kneading the foregoing dryingcomponents with, for instance, a thermoplastic resin and then moldingthe resulting blend into films and may be used alone or after laminatingthem with the protective member, upon the practical use. Examples ofsuch thermoplastic resins are polyethylene, polypropylene,polycarbonate, polyamide, ethylene-vinyl acetate copolymer,ethylene-methyl acrylate copolymer, polyvinyl chloride, polystyrene,polyester terephthalate and polyvinylidene chloride. These thermoplasticresins may be used alone or in any combination.

In case where the drug is decomposed through oxidation, a deoxygenationagent may simultaneously be enclosed or incorporated into the drug unitin addition to the foregoing drying component.

Drugs usable herein are anymedicine used in any therapeutic field, whichis soluble or dispersible in water and, in particular, physiologicallyactive substances having a molecular weight ranging from 1×10² to 1×10⁶can widely be used in the present invention. Examples of drugs arenarcotics, analgesics, anorexics, anthelmintics, drugs for asthma,anticonvulsants, antidiarrheals, antineoplasticagents, drugs forParkinson's diseases, antipruritics, sympatholytic agents, xanthinederivatives, drugs for angiocardiac diseases such as calcium channelblockers, antipyretics, β-blockers, antiarrhythmic agents, hypotensivedrugs, diuretics, vasodilators for blood vessels including systemic,coronary, peripheral and cerebral vessels, drugs for hemicrania, drugsfor drunkness and motion sickness, antiemetics, central nervous systemstimulants, drugs for cough and common cold, decogestants, diagnostics,drugs for hormonotherapy, parasympatholytic agents, parasympathomimeticagents, psychostimulants, sedatives, tranquilizers, anti-inflammatoryagents, anti-arthritic agents, anti-spasmodics, antidepressants, drugsfor treating psychosis, drugs for treating dizziness, anti-anxietyagents, narcotic antagonists, carcinostatic agents, hypnotics,immunosuppressors, muscle relaxants, antiviral agents, antibiotics,anorexics, antiemetics, anti-cholinergic agents, antihistamic agents,contraceptives, antithrombotic agents, bone-absorption suppressors andosteogenesis-promoting agents. However, the present invention is notrestricted to these specific drugs listed above. These drugs may be usedalone or in any combination.

Specific examples of these drugs include steroids such as estradiol,progesterone, norgestrel, levonorgestrel, norethindrone,medroxy-progesterone acetate, testosterone and esters thereof; nitrogroup-containing compounds and derivatives such as nitroglycerin andisosorbide dinitrates, nicotine, chlorpheniramine, terfenadine,triprolidine and hydrocortisone; oxicam derivatives such as piroxicam;acetic acid or propionic acid derivatives such as indometacin,flurbiprofen, felbinac and diclofenac, ketoprofen; mucopolysaccharidessuch as thiomucase, buprenorphine, fentanyl, naloxone, codeine,lidocaine, dihydroergotamine, pizotyline, salbutamol and terbutaline;prostaglandins such as misoprostol, enprostil, omeprazole andimipramine; benzamides such as metoclopramine, scopolamine andclonidine; dihydropyridines such as nifedipine, verapamil, ephedrine,pindolol, metoprolol, spironolactone, nicardipine HCl and calcitriol;thiazides such as hydrochlorothiazide and flunarizine; sydnone iminessuch as molsidomine; sulfated polysaccharides such as heparin fractionsand proteins; and peptides such as insulin and homologues thereof;calcitonins and homologues such as elcatonin, protamin and glucagone;globulins, angiotensin I, angiotensin II, angiotensin III, lypressin,vasopressin, somatostatin and homologues thereof; growth hormones andoxytocin; as well as, if necessary, pharmaceutically acceptable saltsthereof with acids or bases. Preferred are, for instance, narcotics,hormones, proteins, analgesics, or other low molecular weight cations.More preferably, examples of drugs include peptides or polypeptides suchas insulin, calcitonin, calcitonin-related genetic peptides,vasopressin, desmopressin, protirelin (TRH), adrenocorticotropichormones (ACTH), luteinizing hormone-release hormones (LH-RH), growthhormone-release hormones (GRH), nerve growth factors (NGF) and otherrelease factors, angiotensins, parathyroid hormones (PTH), luteinizinghormones (LH), serumal gonadotropin, hypophyseal hormones (such as HGH,HMG, HCG), growth hormones, somatostatin, somatomedin, glucagon,oxytocin, gastrin, secretin, endorphin, enkephalin, endothelin,cholecystokinin, neurotensin, interferon, interleukin, transferrin,erythropoietin, superoxide dismutase (SOD), filgrastim (G-CSF),vasoactive-intestinal-polypeptides (VIP), muramyl dipeptides,corticotropin, urogastroneandatrialsodiumuragoguepeptides (h-ANP).However, the present invention is not restricted to these specific drugsat all. Among these, particularly preferred are peptide hormones. It isalso possible to optionally use adsorption-inhibitory agents such asbenzalkonium chloride, BSA (bovine serum albumin) and monolauric acid.

In the present invention, at least one of the foregoing drugs and saltsthereof may be supported on the drug support. In addition, the amount ofthe drug is determined depending on a particular drug in such a mannerthat, upon administration thereof to a patient, a predeterminedeffective blood concentration is maintained over an effective period oftime and the size of the iontophoresis device as well as the area of thedrug-delivery surface thereof are determined in proportion thereto.

We will now explain, in detail below, the structures of parts other thanthe drug unit detailed above.

FIG. 7 is a diagram showing an embodiment of the configuration of acurrent-generating portion Ia, in which (a), (b) and (c) are a view ofthe surface, a view of the back face and a cross sectional view of thecurrent-generating portion, respectively. The current-generating portionIa is a plastic molded body having therein a built-in current-controlcircuit. A current-control switch 1 is arranged on thecurrent-generating portion, while a female electrode terminal 2 (oneeach of the terminal on the sides of the anode and cathode) is arrangedbelow the current-generating portion. This current-generating portion Iais preferably designed such that no physical burden due to the size andweight thereof is given to a patient.

More specifically, the current-generating portion is constituted by aself-oscillator circuit provided with a built-in small-sized cell, anappropriate high voltage-generating circuit connected to the oscillatorcircuit and a control circuit for operating and controlling thesecircuits. It is also possible to incorporate a BOLUS button fortemporarily increasing the injection rate for a drug into thecurrent-generating portion. This is quite useful function when ananalgesic is administered to a patient and the patient desires for atemporary increase in the dose thereof in proportion to the degree ofhis pains.

Moreover, the control circuit is, for instance, designed in such amanner that the circuit permits the manual on/off switching in order toallow the on-demand medication regime and the on/off switching at aperiod adapted for the biological circadian rhythm and the pattern atintervals of 24 hours. In addition, the control circuit may be equippedwith a built-in microprocessor and therefore, the circuit permits themodification of the level of the current and the wave form such aspulses and sinusoidal waves to be applied over a predetermined time.Moreover, the control circuit may comprise a biosensor or a certain kindof feedback system for monitoring the biosignals emitted by a patient,evaluating the treating method and adjusting the amount of the drug tobe administered to the patient in response to the results of theevaluation. It is also possible to incorporate one or more programspredetermined by the maker of the drug, a physician or a patient intothe control circuit.

FIG. 8 is a diagram showing an embodiment of the configuration of anintegrated electrode portion Ib, in which (a), (b), (c) and (d) are aview of the surface, an internal view, a view of the back face and across sectional view of the electrode portion, respectively. Theintegrated electrode portionIbhasabackinglayer4consistingof afilmofapolyester or a polyolefin such as polypropylene, or a molded body ofsuch a film laminated with an aluminum layer. Printed electrode portions6, 7 are arranged on the molded backing layer 4 and they are formed byprinting silver (on the anode side) and silver chloride (on the cathodeside). Moreover, two insertion openings 5 (one each of the opening onthe sides of the anode and cathode) for conductive snap connectors arepositioned on the printed electrode portion at the center of the backinglayer.

Conductive layers 10, 11 are formed on the integrated electrode portionIb in such a manner that they are adjacent to the printed electrodeportions 6, 7 and the material used for forming these layers is awater-retentive material such as a nonwoven fabric or a hydrophilicpolymer, which comprises an electrolyte. In this respect, the conductivelayer 11 on the donor side (in this Example, the layer on the anodeside) also serves as a moisture supply source for the drug accommodatedin the drug unit (Ic-1), upon activation. Moreover, the conductivelayers are packaged with a water-impermeable cover material 9 througheasily peeled heat seal in order to prevent any moisture evaporationduring storage. Further an adhesive film 3 such as a medical adhesivetape is applied onto the periphery of the backing layer 4 for thepurpose of fixing the pharmaceutical preparation to a drug-applicationsite and a liner 8 is fitted to the adhesive film during storage.

Incidentally, the integrated electrode portion Ib may have a knownelectrode structure. For instance, usable herein are materials such asplatinum black, titanium, carbon, aluminum, iron, lead,carbon-containing conductive rubber and conductive resins, with platinumelectrodes, silver electrodes, silver chloride electrodes or the likebeing particularly desirable.

The foregoing cover material 9 is not restricted to any particular oneinsofar as it is formed from a water-impermeable material. For instance,the cover material is formed from a film laminated with an aluminumlayer. If a highly sealed condition by heat sealing is required, thecover material is laminated with a plurality of films such as thosedescribed above in connection with the liner or it is coated withanother polymer resin. This makes the peeling off of the cover materialeasy. For instance, there can be used an easily peelable laminate film.It is desirable that the laminate film have a peel strength at 180degrees of 2000 g or less.

A pressure-sensitive adhesive is used as an adhesive material for theadhesive film 3 (the adhesive layer 13 at the peripheryof the drugsupport). Anypressure-sensitive adhesive may be used herein inasmuch asthey can maintain the iontophoresis device on the surface of the skin ormucous membrane of a patient, while the device is brought into closecontact therewith, they have an adhesive force sufficient for ensuringgood adhesion of the drug support to the drug-dissolving portion andthey are physiologically acceptable for the skin. Specific examplesthereof are acrylic adhesives comprising homopolymers or copolymers ofalkyl acrylates whose alkyl moiety has 4 to 18 carbon atoms, such asacrylic acid, methyl acrylate, ethyl acrylate, 2-ethylhexyl acrylate,isooctyl acrylate, decyl acrylate, lauryl acrylate and stearyl acrylate;methacrylic adhesives comprising homopolymers or copolymers of alkylmethacrylates whose alkyl moiety has 4 to 18 carbon atoms, such asmethyl methacrylate, ethyl methacrylate, butyl methacrylate,2-ethylhexyl methacrylate, isooctyl methacrylate, decyl methacrylate,lauryl methacrylate and stearyl methacrylate; silicone type adhesivessuch as those comprising polyorganosiloxane and polydimethyl-siloxane;and rubber type adhesives such as those comprising natural rubber,polyisobutylene,. polyvinyl ether, polyurethane, polyisobutylene,polybutadiene, styrene-butadiene copolymer, styrene-isoprenecopolymerandstyrene-isoprene-styreneblock copolymer. Moreover, theadhesive material may, if necessary, comprise a tackifier and asoftening agent.

These adhesive materials are first mixed in a mixing machine such as akneader or a mixer and then spreaded on a support film, before thepractical use. In addition, in case of the adhesive layer 13 for theperiphery of the drug support, the adhesive materials are used accordingto, for instance, amethod comprising the step of directly and partiallyapplying them to the drug support; or amethod comprising the steps ofspreading them on a thermoplastic support film and then fixing thesupport film to the drug support through heat seal. If the drug supporthas insufficient flatness, the latter method is preferably used and theresulting adhesive layer permits the inhibition of any penetration ofair upon activation of a drug present in the drug support. In thisconnection, materials for the support film usable herein may be thosefor the backing layer 4 as will bedetailedbelow, but it is important toselectandusematerials free of any interaction with the drug and/or freeof any adsorption of the drug. Moreover, in case of the adhesive film 3,preferably used herein are foams of synthetic resins, which have highgas permeability and which are quite agreeable to the touch. On theother hand, in case of the adhesive layer 13 for the periphery of thedrug support, preferred are polyolefinic films having a low meltingpoint.

A material for the backing layer 4 herein used may be an effectivecomponent-impermeable material. Examples thereof are films, sheets andfoams of synthetic resins such as polyethylene, polypropylene,polyethylene terephthalate, polyvinyl chloride, polyvinylidene chloride,plasticized vinyl acetate copolymer, plasticizedvinylacetate-vinylchloride copolymer, polyamide, cellophane, cellulose acetate, ethylcellulose, polyester, polycarbonate, polystyrene, polyurethane,polybutadiene, polyimide, poly-acrylonitrile, polyisoprene, polystyrenederivatives, ethylene-vinyl acetate copolymer, ethylene-polyvinylalcohol copolymer, fluoroplastics, acrylic resins and epoxy resins,which may be used alone or in the form of a laminate of at least two ofthem.

In addition, the films, sheets, foams or the like of these syntheticresins may be laminated with metal foils such as aluminum and tin foils;nonwoven fabrics and synthetic paper or may be covered with depositedaluminum layers and ceramic coatings. Moreover, if closed package by,for instance, heat sealing is required, they may be laminated with aheat-sealable material.

The electrode portion may be deposited on the backing layer by, forinstance, a method comprising the steps of mixing an electrode materialwith, for instance, a print ink for electric wirings, applying the printink to a material for the backing layer and then drying the same; amethod comprising the steps of spreading an electrode material and thenfixing the material to the backing layer; a method comprising the stepof depositing an electrode material onto the backing layer; or a methodin which the electrode portion is formed by photo-etching an electrodematerial applied onto the backing layer. In addition, an insulatinglayer may additionally be applied onto a part of the printed electrodelayer, which may come in contact with the skin of a patient.

The conductive layer may simply comprise water or may comprise at leastone member selected from the group consisting of soft porous materialssuch as ion-exchangeable polymers, foaming materials and sponge andwater-absorptive polymers. Moreover, the conductive layer may comprisean electrolyte such as sodium chloride, potassium chloride, sodiumcarbonate, phosphoric acid or sodium citrate; or a pH-buffering agentsuch as acetic acid, sodium acetate, phosphoric acid, sodium phosphate,citric acid or sodium citrate, for the improvement of the electricconductivity thereof.

Specific examples of the preferably used conductive layers in generalinclude nonwoven fabric, paper, gauze, absorbent wadding, polyethyleneor polypropylene having open cells, polyvinyl acetate, porous films andfoams of, for instance, polyolefin foams, polyamide foams andpolyurethane, natural polysaccharides such as karaya gum, tragacanthgum, xanthane gum, starches, gum arabic, locust bean gum, gellan gum,guar gum and carrageenan; gelatin, pectin, agar, sodium alginate orpolyvinyl alcohol and partially saponified products thereof; polyvinylformal, polyvinyl methyl ether and copolymers thereof;polyvinylpyrrolidoneandcopolymers thereof; aqueous or water-solublecellulose derivatives such as sodium carboxy-methyl cellulose, methylcellulose, hydroxyethyl cellulose, hydroxymethyl cellulose,hydroxypropyl methyl cellulose, hydroxypropyl cellulose and celluloseacetate phthalate; carboxyvinyl polymer, polyacrylamide andpoly-acrylamide derivatives, casein, albumin, chitin, chitosan,polyacrylic acid, sodium polyacrylate, poly-HEMA, poly-HEMA derivatives,methoxyethylene-maleic acid anhydride copolymer, N-vinyl acetamide,N-vinyl acetamide and acrylic acid and/or acrylic acid salt copolymers,as well as crosslinked products thereof, water-soluble polymersoptionally plasticized with, for instance, ethylene glycol or glycerinand hydrogels thereof. However, the present invention is not restrictedto these specific ones. In addition, the foregoing materials may be usedin any combination of at least two of them. Moreover, it is alsopossible to use, if necessary, benzalkonium chloride BSA (bovine serumalbumin) and adsorption-inhibitory agent such as monolauric acid.

Furthermore, the conductive layer may also comprise an ion-exchangeablepolymer for the removal of ions competitive with a desired drug. Suchion-exchangeable polymers usable herein are appropriately selected fromanion-exchange polymers, cation-exchange polymers and ampholyticion-exchange polymer, depending on the ionic properties of eachparticular drug. In addition, the ion-exchangeable polymer may beincorporated into the conductive layer by, for instance, a methodcomprising the step of dispersing fine powder of an ion-exchangeablepolymer in the foregoing polymer to thus form the mixture in a gel-likeform or a method, which makes use of a product of such anion-exchangeable polymer previously formed into a film, but the presentinvention is not restricted to these methods at all.

The capacity of the conductive layer on the donor electrode side(drug-dissolving portion) is not particularly restricted to a specificrange, but depends on, for instance, the size of the electrode portionand the optimum amount of water required for dissolving a drugaccommodated in the drug support, or the water content of the absorptivemember of the drug-dissolving portion. In this respect, however, if theamount of water is too large, it may cause leakage of thedrug-dissolving liquid, while if it is too small, the drug present inthe drug support cannot completely be dissolved and the drug efficacy iscorrespondingly reduced. Therefore, the amount of water is desirably onthe order of the maximum water absorption of the drug support. If ahydrogel is used in the drug-dissolving portion, the syneresis thereofparticularly preferably ranges from 10 to 100 mg/cm². Moreover, thehydrogel should have such a gel strength that the gel is never brokenduring the assemblage of the device and during the application thereofto the skin and therefore, the hydrogel desirably has a gel strengthranging from 400 to 1500 g/cm².

The amount of water required for dissolving a drug present in the drugsupport is, in advance, controlled in the drug-dissolving portion. Thus,a precise amount of water can certainly and rapidly be supplied to thedrug support at any time upon the practical use and this makes thetherapeutic effect accurate. Moreover, this can also simplify thetreating operations and reduce the treating time.

FIG. 9 is a diagram showing an embodiment of the configuration of aconductive snap connector Id, in which (a) and (b) are a view of thesurface and a cross sectional view of the connector, respectively. Thisconnector Id is provided with two electrode terminals 25 (male) on anelectrode terminal-fixing table 24 and they are designed in such amanner that they can be connected to the electrode terminals 2 (female)of the current-generating portion Ia, after the assemblage of thedevice.

The current-generating portion is connected to the electrode portionsuch that the latter is sandwiched in between the electrode terminal onthe current-generating portion side and that on the conductive snapconnector side. The electrode terminal on the conductive snap connectorside comes in contact with the printed electrode portion (either of theanode and cathode) of the electrode portion due to the connection.Accordingly, the current-generating portion and the electrode portioncan electrically be charged and the electrical connection can thus beestablished.

In addition, if they are connected, while inserting the drug unit inbetween the current-generating portion and the electrode portion uponthe assemblage of the device, the electrode terminal also serves as ameans for mechanical connection for the purpose of positioning oraligning the electrode portion with the drug unit. Thus, the connectionof the current-generating portion to the conductive snap connectorthrough the electrode terminals is quite important as a means forassembling the device.

In respect of the modes of the connection of the current-generatingportion to the electrode portion, the device may be operated in acordless mode or a remote control mode using a cord. In case of theformer, a small-sized current-generating portion is directly connectedto the electrode portion when it is intended to carry out an easy andquick treatment. Besides, in case of the latter, the current-generatingportion is connected to the electrode portion through an exclusiveconnecting cord when it is intended to carry out a treatment whileoperating the current-generating portion at hand. In this connection,connection means are fitted to the both sides of the connecting cord forthe purpose of connecting the current-generating portion to theconductive snap connector. In this embodiment, electrode terminals (bothanode and cathode terminals) are incorporated into a plastic molded bodyso that it serves to connect the terminals, to each other, of thecurrent-generating portion and the conductive snap connector. In thisrespect, the connection means is not restricted to an electrode terminaland the shape and the connection mode thereof may be arbitrarily bechanged. Preferably, the connection means on the conductive snapconnector side has such a structure that the drug portion and theelectrode portion are in line with each other and they can firmlymaintain a desired arrangement.

FIG. 10 is a diagram showing an embodiment of the configuration of anauxiliary stand for assemblage Ie-1, in which (a) and (b) are a view ofthe surface and a cross sectional view of the connector, respectively.The auxiliary stand Ie-1 for assemblage is designed in such a mannerthat it possesses a space 27 for accommodating the electrode portion,whose shape corresponds to that of the backing layer 4 of the electrodeportion and that it has two rods 26 used for positioning upon theassemblage of the device. Materials for the auxiliary stand forassemblage are not restricted to any specific one insofar as they areselected from those capable of being shaped and/or processed, such aspaper, metals, wood and plastic films (such as polypropylene, Teflon andpolyvinyl chloride films), but preferred are plastic films having highshape-retention ability and a thickness of 0.5 mm or more.

This auxiliary stand for assemblage is devised to make, easy, theoperations requiredwhen a patient assemble this device. In thisembodiment, the stand is provided with a space 27 for accommodating theelectrode portion, whose shape corresponds to that of the backing layer4 of the electrode portion and therefore, the electrode portion can bedisposed on the precise position on the auxiliary stand. Theelectrode-accommodating space 27 is also important in that it canprevent any damage of the electrode portion possibly encountered whenthe device is assembled.

In addition, the auxiliary stand may be provided with alignment rods 26.The alignment rod 26 makes it easy to align the electrode portion withthe drug unit upon the assemblage of the device and is effective foreliminating the occurrence of any artificial error.

FIG. 11 is a diagram showing an embodiment of the configuration of anauxiliary stand Ie-2 for assemblage, in which (a) and (b) are a view ofthe surface and a cross sectional view of the connector, respectively.The auxiliary stand Ie-2 for assemblage is designed so as to have aspace 29 for accommodating the current-generating portion, whose shapeis in conformity with that of the current-generating portion Ia. Thespace 29 is provided with a means 28 for fixing the current-generatingportion to the auxiliary stand Ie-2.

In this connection, the auxiliary stand for assemblage may have astructure combined with those described above depending on the shape andthe procedures for assemblage of the device, and the shape thereof canfurther be modified. Materials for the auxiliary stand are notrestricted to any specific one insofar as they are selected from thosecapable of being shaped and/or processed, such as paper, metals, woodand plastic films (such as polypropylene, Teflon and polyvinyl chloridefilms), but preferred are plastic films having a high shape-retentionability and a thickness of 0.5 mm or more.

FIG. 12 is a diagram showing an embodiment of the method for assemblingan iontophoresis device, which makes use of a drug unit Ic-1 accordingto the embodiment 1, in which (a) shows the first half of the assemblingprocess and (b) shows the second half of the assembling process,respectively.

A current-generating portion Ia is incorporated into a space 29 foraccommodating the current-generating portion on an auxiliary stand Ie-2for assemblage so that an electrode terminal 2 (female) looks upward asindicated by an arrow {circle around (1)} in FIG. 12(a) and fixed to thestand by means 28 for fixing. Then an electrode portion Ib is disposedwhile it coincides with a recess of the auxiliary stand Ie-2 asindicated by an arrow {circle around (2)} in FIG. 12(a) and thereafter acover material 9 of the electrode portion Ib is peeled off to thusexpose a drug-dissolving portion 11 as indicated by an arrow {circlearound (3)} in FIG. 12(a). Subsequently, the electrode portion Ib isbrought into contact with a drug unit Ic-1 using a conductive snapconnector Id as indicated by arrows {circle around (4)} and {circlearound (5)} in FIG. 12(a) in such a manner that they are in line witheach other and thereafter a liner 17 of the drug unit Ic-1 on theelectrode portion side (which has been folded along a perforation) ispeeled off as indicated by an arrow {circle around (6)} in FIG. 12(a).At the same time, a drug support 14 of the drug unit is connected to thedrug-dissolving portion 11 of the integrated electrode portion as shownby an arrow {circle around (7)} in FIG. 12(a), whereby the moisturepresent in the drug-dissolving portion 11 penetrates into the drugsupport 14 and the drug present therein is thus dissolved.

Thereafter a liner 12 of the drug unit on the skin side is pulled outfrom the conductive snap connector Id as indicated by an arrow {circlearound (8)} in FIG. 12(b), then a liner 8 for an adhesive film is peeledoff immediately before the application of the device as indicated by anarrow {circle around (9)} in FIG. 12(b) and finally the device isdetached from the auxiliary stand. Thus, the iontophoresis device can beapplied to an application site without any pre-treatment to thusinitiate the treatment of a patient. The iontophoresis device accordingto this embodiment permits the inhibition of any movement of the drugand the drug-dissolving liquid towards the peripheral regions and theprevention of the occurrence of any non-uniform, electrically chargedstate due to air-admixture.

FIG. 13 is a diagram showing an embodiment of the method for assemblingan iontophoresis device, which makes use of a drug unit Ic-2 accordingto Example 2 of the present invention, in which (a) shows the first halfof the assembling process and (b) shows the second half of theassembling process, respectively.

An electrode portion is positioned on an auxiliary stand Ie-1 using analignment rod 26 of the stand as indicated by an arrow {circle around(1)} in FIG. 13(a) and then a cover material 9 of the electrode portionIb-1 is peeled off to thus expose a drug-dissolving portion 11, asindicated by an arrow {circle around (2)} in FIG. 13(a). Further a liner17 of the drug unit Ic-2 on the electrode portion side is peeled off, asindicated by an arrow {circle around (3)} in this figure. Thereafter,the electrode portion Ib-1 is brought into contact with the drug unitIc-2 while they are in line with one another, as indicated by an arrow{circle around (4)} in the same figure to thus join the drug support 14of the drug unit and the drug-dissolving portion 11 of the integratedelectrode portion, as indicated by an arrow {circle around (5)} in thisfigure. Thus, the moisture present in the drug-dissolving portion 11penetrates into the drug support 14 and the drug present therein iscorrespondingly dissolved. Subsequently, the pharmaceutical preparationis removed from the auxiliary stand Ie-1.

Then, after joining a conductive snap connector Id and acurrent-generating portion Ia as indicated by an arrow {circle around(7)} in FIG. 13(b) and a liner 12 of the drug unit on the skin side ispeeled off immediately before the application thereof as shown by anarrow {circle around (8)} in the same figure, a liner 8 for an adhesivefilm is peeled off as indicated by an arrow {circle around (9)} in thisfigure. Thus, the iontophoresis device can be fitted to an applicationsite without any pre-treatment and accordingly, a treatment of a patientcan be initiated. The assemblage of the device according to theprocedures described above would permit the inhibition of any movementof the drug and the drug-dissolving liquid towards the peripheralregions and the prevention of the occurrence of any non-uniform,electrically charged state due to air-admixture. Moreover, the use of amolded liner likewise permits the inhibition of any adsorption of thedrug solution onto the liner. Moreover, in this embodiment, a dryingagent can be positioned within the drug unit and therefore, the deviceof the present invention permits the miniaturization of packages and theimprovement in stability of the drug to be incorporated into the device.

TEST EXAMPLE 1

Experiments on Drug Adsorption on Drug Protective Member upon Assemblageof Device

In this Test Example, the drug units of Examples 1 and 2 and ComparativeExample 1 were inspected for the amounts of drugs adsorbed on theprotective members when the drug units were activated. In this respect,the drug units and the electrode portions used herein and the device ofComparative Example 1 were as follows:

Drug Unit

Human parathyroid hormone (hPTH (1-34), 400 μg per sheet of drugsupport) was supported on a drug support (hydrophilic DURAPORE, averagepore size: 5 μm; porosity: 70%; effective surface area: 2.5 cm²) in itsdry condition to thus give each drug unit.

On the other hand, the drug unit of Comparative Example 1 had astructure identical to that of Example 1, except that a protectivemember (liner 17 on the electrode portion side, liner 12 on the skinside) free of any adsorption-inhibitory treatment was used.

Electrode Portion

There was introduced 1.5 g of a 1.5% agar gel containing a citric acidbuffering solution (33 mM, pH 5) into a conductive layer(drug-dissolving portion) adjacent to 2.5 cm² of a donor electrode(silver-printed portion) and 1.0 g of sodium chloride-containingpolyvinyl alcohol (UF-250G available from Unitika, Ltd.) was introducedinto areference electrode (silver chloride-printed portion) to thus givean electrode portion.

Procedures of Experiment

After assembling the drug unit and the electrode portion according tothe method for assemblage described in Embodiments 1 and 2, the liner ofthe drug unit on the skin side was peeled off after one minute from theassemblage, the drug adsorbed on the unit was extracted with 1 ml of a0.5 mM acetic acid buffering solution (containing 0.9% sodium chlorideand 0.01% of benzalkonium chloride; pH 4) and then the amount of thedrug adsorbed on the liner on the skin side was determined by the(reverse phase) high performance liquid chromatography. (n=4).Incidentally, the assemblage in Comparative Example 1 was carried outaccording to the assemblage method used in Example 1. The results thusobtained are summarized in the following Table 1.

TABLE 1 Shape of Adsorption- Amt. of Drug Protective Inhibitory AdsorbedMember Material Treatment (%) Example 1 Flat Liner PolyethyleneTreatment 0.10 ± 0.13 terephthalate with Silicone Example 2 MoldedPolypropylene Treatment Not Detected Liner with Silicone ComparativeFlat Liner Polyethylene — 3.57 ± 1.89 Example 1 terephthalate

The data listed in Table 1 clearly indicate that about 4% of the drug isadsorbed on the liner on the skin side in Comparative Example 1, whilealmost no drugs are adsorbed on the liners on the skin side upon theassemblage, in Examples 1 and 2 which make use of the protective memberssubjected to the adsorption-inhibitory treatment. Moreover, it was alsoconfirmed that the use of a molded liner as a protective memberpermitted further reduction of the influence of the liner on the drugsupport. In addition, a drug solution was applied to the drug supportthrough an opening for the application of a drug solution and then driedto examine the loss in the drug content. (Test results were not given).As a result, there was not observed any loss in the drug content forboth Examples 1 and 2. In other words, a drug solution can be appliedafter the arrangement of a protective member and therefore, any drugloss during preparation (due to exogenous factors) can be prevented.

TEST EXAMPLE 2

Test on Inhibition of Diffusion of Drug Solution After Assemblage ofDevice

In this Test Example, the drug units of Example 2 and ComparativeExample 2 were inspected for the amount of a drug, which diffused from adrug support to the periphery thereof when the units were activated. Inthis respect, the drug units and the electrode portions used herein andthe device of Comparative Example 2 were as follows:

Drug Unit

The drug units of Example 2 and Comparative Example 2 used herein wereidentical to that used in Example 1. In this respect, however, the unitof Example 2 was subjected to a drug diffusion-inhibitory treatmentwhile that of Comparative Example 2 was free of such a treatment.

Electrode Portion

The electrode portions used in this Test Example were the same as thatused in Example 1.

Procedures of Experiment

After assembling the drug unit and the electrode portion according tothe method for assemblage used in Embodiment 2, the drug unit was peeledoff after 5 minutes and 15 minutes from the assemblage, followed bydrying. After the drying, the drug unit (drug support) was divided intothe exterior and the interior along the portion subjected to thediffusion-inhibitory treatment as a boundary to thus determine theamount of the drug diffused to the exterior of the portion subjected tothe diffusion-inhibitory treatment (non-conductive portion). The amountof the drug was determined by extracting the drug adsorbed on eachsample with 1 ml of a 0.5 mM acetic acid buffering solution (containing0.9% sodium chloride and 0.01% of benzalkonium chloride; pH 4) and thensubjecting the resulting extract to the (reverse phase) high performanceliquid chromatography. (n=3). The results thus obtained are summarizedin the following Table 2.

TABLE 2 Diffusion- Amt. of Amt. of Inhibitory Processing Diffused DrugDiffused Drug Treatment Mode (5 min) (15 min) Example 2 Yes Thermal NotDetected   0.20 ± 0.40 μg Com-    (0.05 ± 0.10%) pression (Ma-1) Compar-No — 200.33 ± 7.08  183.99 ± 31.43  ative (55.37 ± 1.96%) (50.85 ±8.69%) Example 2

It was confirmed, from the data listed in Table 2, that about 50% of thedrug was found to diffuse to the non-conductive portion in ComparativeExample 2 and that almost no drug diffused to the non-conductive portionand the drug was maintainedwithin the effective area in Example 2. Theresults clearly indicate that, in a device free of anydiffusion-inhibitory treatment, a reduced amount of the drug ispractically used in the treatment of a patient after the assemblage ofthe device and therefore, a desired drug efficacy cannot be expected. Inother words, these results suggest that the diffusion-inhibitorytreatment is quite effective.

TEST EXAMPLE 3 Determination of Blood Concentration of hPTH (1-34)

In this Test Example, the drug units of Examples 1 and 2 and ComparativeExample 3 were activated, then practically used and thereafter theconcentrations of hPTH (1-34) in the sera were determined. In thisconnection, the drug units and the electrode portions herein used andthe device of Comparative Example 3 were as follows:

Drug Unit

Human parathyroid hormone (hPTH (1-34), 400 μg per sheet of drugsupport) was supported on a drug support (hydrophilic DURAPORE, averagepore size: 5 μm; porosity: 70%; effective surface area: 2.5 cm²) in itsdry condition to thus give each drug unit. As will be seen from Table 3,the drug units of Examples 1 and 2 hereinusedwere subjected to adrugdiffusion-inhibitory treatment (Ma-1) and an air-exhausting treatment(Mb-1, Mb-2). On the other hand, the drug unit of Comparative Example 3was subjected to a drug diffusion-inhibitory treatment (Ma-1), but wasfree of any air-exhausting treatment.

TABLE 3 Shape of Adsorption- Diffusion- Air- Protective InhibitoryInhibitory Exhausting Member Treatment Treatment Treatment Example 1Flat Liner Treatment with Yes (Ma-1) Yes (Mb-1) Silicone Example 2Molded — Yes (Ma-1) Yes (Mb-2) Liner Comparative Flat Liner Treatmentwith Yes (Ma-1) — Example 3 Silicone

Electrode Portion

The electrode portion herein used was identical to that used in TestExample 1.

Procedures of Experiment

SD rats (male, 6-week-old) were anesthetized with urethane and hairs onthe abdominal skin was removed (hair clipper-shaver). Then each drugunit was activated according to the assemblage method used in Example 1or 2 and subsequently the resulting device was fitted to the abdomen ofthe SD rat and the electrical charging thereof was initiated. Theelectrical charging was carried out using a 0.25 mA DC pulse currenthaving a frequency of 40 kHz and an on/off ratio (3/7) and continuedover 60 minutes. Blood samples were intrajugularly collected after theelapse of predetermined times, followed by centrifugation thereof togive each corresponding sample of the serum. The concentrations (pg/ml)of hPTH (1-34) in the sera were determined by the radioimmunoassay.

The results thus obtained are plotted on FIG. 14 and FIG. 14 isaccordingly a graph showing changes, with time, of the concentration ofhPTH (1-34) in the serum observed in Test Example 3. (n=4). When thesamples of this Test Example were activated, it was confirmed, inExamples 1 and 2, that the air in the device was removed and thedrug-dissolving portion was evenly and uniformly brought into contactwith the drug support. On the other hand, air remained in the device andit was never removed even when the device was applied to the skin, inthe device of Comparative Example. The experimental results obtainedusing these samples indicate that the blood concentration observed inComparative Example 3 is generally lower than those observed in Examples1 and 2 and widely varies. In other words, it would be concluded thatthe blood concentration is greatly affected by the presence of air inthe device. Accordingly, these results clearly suggest that theair-exhausting treatment is quite effective.

As has been discussed above in detail, the iontophoresis deviceaccording to the present invention comprises a drug support subjected toa drug solution-diffusion-inhibitory treatment and therefore, the devicesuitably permits the prevention of any drug loss during producing,storing, assembling and using (treating a patient) the device. Thedevice accordingly permits the reduction of any possibility of producingsubstandard products during manufacture, the improvement of the drug inthe long-term stability during storage and the inhibition of any leakageof a drug solution and/or any migration thereof during application.Moreover, the drug unit is subjected to an air-exhausting treatment as ameans for eliminating any puddle of air in the device encountered whenthe device is assembled and therefore, the device allows the uniformdissolution of the drug and the uniform electrical charging of thedevice. Further, the device is designed in such a manner that a dryingcomponent may be disposed within the drug unit and accordingly, thelong-term stability of the drug can be improved and the manufacturingprocess can be simplified. The foregoing indicates that theiontophoresis device according to the present invention permits accuratesupply of water required for the dissolution of the drug to the drugsupport, which has been stored under highly stable environment and alsopermits the prevention of any loss of the resulting drug solution.Consequently, the device of the present invention has high biologicalavailability.

Industrial Applicability

The iontophoresis device and the drug unit according to the presentinvention are useful for effective use of a drug incorporated into adrug support and are suitably used for iontophoresis in the medicalfield.

What is claimed is:
 1. An iontophoresis device comprising adrug-dissolving portion having a function of activating a drug; and adrug unit, which is subjected to at least one treatment selected from adrug diffusion-inhibitory treatment and an air-exhausting treatment,having a drug support removably joined with the drug-dissolving portion.2. The iontophoresis device according to claim 1, wherein the drugdiffusion-inhibitory treatment includes a resin member and/or athermally compressed portion disposed at the periphery of the drugsupport.
 3. The iontophoresis device according to claim 1, wherein theair-exhausting treatment is to form an air vent hole at the periphery ofthe drug support.